Imaging studies are the cornerstone for tumor localization in patients with Cushing's syndrome caused by ectopic adrenocorticotropin hormone (ACTH) secretion (EAS). Computed tomography (CT) and magnetic resonance imaging (MRI) are used most commonly to localize the source of EAS. However, in 30-50 percent of patients with EAS the source of ACTH secretion cannot be found despite repeated studies over time. Up to half of these patients do not respond to medical therapy of hypercortisolism and must undergo bilateral adrenalectomy with lifelong replacement therapy. Thus, there is a need for improved imaging techniques to identify ACTH-secreting tumors.[unreadable] [unreadable] Nuclear medicine techniques enable in vivo imaging of physiological and pathophysiological processes, and among these techniques, positron emission tomography (PET) studies are increasingly used in oncology. We previously evaluated the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) or 111In-DTPA-D-Phe-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi; H-OCT), and found that FDG-PET did not detect tumors that were occult on CT/MRI. H-OCT rarely identified a lesion. Thus, conventional modalities of CT and MRI should be used to image the neck, thorax, and abdomen in these patients. FDG-PET does not provide additional information. H-OCT may be useful when other imaging modalities fail to localize the ACTH-secreting tumor. [unreadable] [unreadable] Currently we are extending these studies to evaluate the utility of 18F- L-3,4-dihydroxyphenylalanine (18F-DOPA) PET to identify these tumors. This compound is a precursor for serotonin production in neuroendocrine tumors, and thus is a good candidate for PET examination since most occult ACTH-secreting tumors are neuroendocrine. [unreadable] [unreadable] The glucocorticoid antagonist mifepristone blocks cortisol action and thus might be an effective treatment of Cushing's syndrome. This hypothesis is being tested in an ongoing clinical trial of patients with presumed ectopic ACTH secretion.